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NH2 + NH3 O O2C S HO 1 N N N N Me + S HO CO2 4 O N N
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+ H3N
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S-Adenosylhomocysteine and S-adenosylmethionine.
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rhabdo- and paramyxoviruses,19 it was concluded that inhibitors of S-adenosyl-Lhomocysteine (1, AdoHcy, Figure 6.1) hydrolase would have an inhibitory effect on the loviruses,20 and that EBO and MBG share common drug targets,14,21 suggesting an agent effective against one will have cross-ef caciousness against the other. In 2000 Bray, Driscoll, and Huggins reported20 that 3-deazaaristeromycin (2, Figure 6.2) and 3-deazaneplanocin A (c3-NpcA, 3), well-known AdoHcy hydrolase inhibitors, showed signi cant activity (high therapeutic index) toward Ebola. In mice, 3 was found to have considerable activity. These results would predict that 3 was acting by inhibiting AdoHcy hydrolase that was, in turn, manifested in decreased viral mRNA methyl capping. A recent paper22 does not refute this but provides further insight into what could be the consequence of incomplete mRNA processing.23 In that regard, 3 is described as causing reversal of the EBO-induced suppression of the innate antiviral interferon (IFN-a)23,24 production in infected mice. This is a very noteworthy observation in developing an immunotherapeutic approach to anti- lovirus agents. This possibility gains support from Bray and his colleagues,20 who stated unlike other IFN inducers (e.g., poly ICLC), which stimulate IFN-a production in both infected and uninfected cells, 3 induces massive IFN-a production only in virus-infected cells. This suggests further studies to overcome undesirable side effects of 3 (e.g., short serum and tissue half-lives25) should be undertaken to provide improved therapeutic candidates based on AdoHcy hydrolase inhibitors (such as 3). This will, in turn, broaden the base of
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2, X=CH 5, X=N
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Various carbocyclic nucleosides.
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understanding the relationship between AdoHcy hydrolase inhibition and IFN-a production suppression upon viral infection, which may not be limited to loviruses, and the role of AdoHcy hydrolase inhibitors in future drug design. This provides the foundation for the research in our laboratories at Auburn. However, before presenting the current status of that effort, some mention of the relationship between messenger RNA (mRNA) and the S-adenosylmethionine (4)/AdoHcy (1) ratio and the role that can play in antiviral drug design is in order.
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In recent years, nucleoside derivatives have been one of the major areas of pursuit in seeking new antiviral agents.26 Out of this, several adenosine analogues have been described. A common characteristic of these compounds is that they are potent product inhibitors of S-adenosyl-L-homocysteine (AdoHcy) hydrolase. AdoHcy catalyzes the reversible hydrolysis of AdoHcy to adenosine (Ado) and homocysteine.27 Inhibition of AdoHcy hydrolase results in accumulation of AdoHcy, which is both the product and a feedback inhibitor of essential S-adenosylmethionine (AdoMet)-dependent methylation reactions (Figure 6.3). Such methylation reactions are required for nal processing of the 50 -capped structure of mRNA (as m7Gppp6AmpApm. . .) from cellular and viral sources.28 30 Therefore, inhibitors of AdoHcy hydrolase may be expected to inhibit maturation of viral mRNAs and, in turn, the production of the requisite proteins and enzymes for generation of progeny virus particles.29 In fact, it has been shown that the vaccinia virus-speci c AdoMetdependant enzymes,31 which catalyze these reactions for processing its mRNAs (i.e., guanine-7-methyltransferase, 20 -O-nucleoside methyltransferase)32,33 are susceptible to inhibition by AdoHcy.34 It is not surprising, therefore, that potential
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NH2 N NH2 O HO2C X OH HO + X=SMe, AdoMet cap Me transferase cap-Me
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AdoHcy hydrolase
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feedback inhibition by AdoHcy
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X=S, AdoHcy Adenosine + homocysteine
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FIGURE 6.3 AdoMet/AdoHcy metabolism.
inhibitors of AdoHcy hydrolase elicit inhibitory activity toward vaccinia virus,19,35 smallpox,36 and Ebola.20 Since AdoHcy hydrolase is a cellular enzyme, it might be expected that the design of AdoHcy hydrolase inhibitors would lead to general suppression of protein synthesis and subsequent host toxicity. In considering how inhibition of AdoHcy hydrolase could succeed in the treatment of lovirus infections without intolerable associated toxicity, two possibilities exist. First, viral infection is likely to lead to increased demand for protein synthesis in virally infected cells relative to uninfected cells. This, in turn, would place a greater demand for methylation of viral mRNA in the infected cells, which would make the methyltransferase reactions more vulnerable to perturbation by increased AdoHcy levels. Borchardt and colleagues35 have provided support for this possibility by reporting that infection of murine L-929 cells with vaccinia virus causes a large increase in the AdoHcy hydrolase activity. Second, qualitative differences between the virally encoded methyltransferases (as is the case for orthopox virus) and those of the uninfected cells can be expected to present different binding domains for the feedback inhibitor AdoHcy and, in turn, different binding constants that could favor preferential inhibition of the viral transferases by AdoHcy over the uninfected cell. In fact, Borchardt has concluded that there exists differences in the AdoHcy-binding sites on AdoMet-dependent methyltransferases and he has reported differential inhibition of the transferases.37 Undoubtedly, prolonged inhibition of AdoHcy hydrolase will overtake general cellular protein synthesis, leading to severe toxicity. Wolfe and Borchardt have noted, however, that a temporary and partial inhibition, while not seriously altering cell function, may allow phosphatases and ribonucleases to destroy the foreign mRNAs. After removal of the AdoHcy hydrolase inhibitor, cellular mRNA cap methylation could resume and full protein synthesis would ensue. 29 Among the most promising antiviral agents based on inhibition of AdoHcy hydrolase are carbocyclic nucleosides,19,38 which are nucleosides wherein the ribofuranose moiety is replaced by a cyclopentane ring [e.g., 5, aristeromycin, which is carbocyclic adenosine, and neplanocin (6) (Figure 6.2).38,39 This structural alteration renders the analogues resistant to phosphorylases, which cleave the glycosidic bond of standard nucleosides, and, consequently, improves their stability as potential medicinal agents.39 Also, conformational changes and stereoelectronic perturbations that occur with replacing the ribofuranose unit with a cyclopentyl ring bring about the unique biological properties of carbocyclic nucleosides.39 In addition to their antiviral properties, carbocyclic nucleosides can serve as substrates for standard nucleoside processing enzymes (e.g., kinases),38,39 as anti-tumor,38 anti-leishmanial,40a and antitrypanosomal40b candidates and as probes to enlighten biochemical processes.41